Malignant Cutaneous Tumors: Cutaneous Lymphoma

From ACP Medicine OnlinePosted 06/07/2006Allan C. Halpern, MD; Patricia L. Myskowski, MD 

Lymphomas may be of B cell or T cell lineage and may involve the skin primarily or secondarily [see 12:IV Principles of Cancer Treatment — omitted]. B cell lymphomas, particularly non-Hodgkin lymphomas, may involve the skin secondarily in advanced disease. They typically appear as reddish-purple subcutaneous plaques or nodules. Primary B cell lymphomas of the skin are even rarer. They appear as reddish nodules that often remain localized to the skin but may progress to systemic disease. The vast majority of primary cutaneous lymphomas fall into the spectrum of cutaneous T cell lymphoma (CTCL).

CTCL includes mycosis fungoides (MF) and Sézary syndrome, which is a leukemic variant of MF.66,67 MF is the largest subset of CTCL; the two terms, however, sometimes are used interchangeably. Another variant of CTCL is associated with human T cell lymphotropic virus type I (HTLV-I) and is part of the spectra of adult T cell lymphoma/leukemia and peripheral T cell lymphoma.66Epidemiology

CTCL is a rare disorder. In the United States, approximately 1,000 new cases of CTCL are diagnosed annually.66 From 1973 to 1984, the incidence of CTCL rose from 0.19 per 100,000 population to 0.42 per 100,000 population. CTCL primarily affects middle-aged adults; the median age at presentation is 50 years.68 The male-to-female ratio is approximately 2:1; blacks are twice as likely as whites to develop CTCL.68Etiology

Host susceptibility and an environmental antigen, perhaps viral, are hypothesized as playing important roles in the pathogenesis of CTCL.66 Genetic factors may be related to major histocompatibility antigens, such as an increase in HLA-DRB1*11 (formerly HLA-DR5) and HLA-DQB1*03.69 Chronic antigenic stimulation (e.g., infection) may play an etiologic role.66 For example, HTLV-I infection may be an etiologic factor in the development of the peripheral T cell lymphoma variant.66Diagnosis

Clinical Manifestations

The clinical manifestations of MF typically evolve over many months to years. In one classic study, the mean duration of symptoms before diagnosis was 7.5 years.70 Flat, erythematous patches, often scaling and occasionally atrophic, begin most commonly on the trunk and thighs, especially in a so-called bathing-trunk distribution [see Figures 6a — omittedand6b — omitted]. Lesions are asymptomatic or mildly pruritic and may spontaneously remit or respond to topical corticosteroid therapy. Patients may also report improvement after sun exposure. As MF progresses, patches tend to enlarge and thicken into plaques. The color may become dark red; in dark-skinned persons, the lesions may initially be hyperpigmented or hypopigmented and may acquire an ery-thematous or violaceous hue. In advanced MF, tumors may develop or transform to a large-cell lymphoma.66,67,71

In approximately 10% of cases, tumors are the initial presentation of CTCL (tumor d'emblé). Generalized erythroderma with circulating atypical T cells (in Sézary syndrome) is the presentation in 5% of CTCL patients.66,67

Physical examination of patients with suspected CTCL includes complete skin examination, including classification of lesions (patch, plaque, or tumor) and extent of body surface area involved. Lymph nodes, the liver, and the spleen should be palpated.

Skin Biopsy

Skin biopsy is necessary for the definitive diagnosis of CTCL. The presence of atypical lymphoid cells with hyperconvoluted cerebriform nuclei in clusters in the epidermis (Pautrier microabscesses) and a bandlike lymphocytic infiltrate in the upper dermis are diagnostic of CTCL.66,67 The malignant cell is a T cell, with most of the cells expressing the pan-T cell markers CD2, CD3, and CD5, as well as frequent deletion of CD7, CD26, or both.66,67,72 The use of T cell receptor gene rearrangement studies to confirm clonality in early disease may be an aid to diagnosis.66 Neither immunophenotypic studies nor electron microscopy may be considered to be definitively diagnostic of CTCL; clinicopathologic correlation is necessary.

Laboratory Studies

The laboratory evaluation for CTCL includes complete blood count, eosinophil count, Sézary cell count, lactic dehydrogenase level, and liver function tests. Bone marrow biopsy is unnecessary in the absence of circulating leukemic cells. HTLV-I testing should be considered for patients with risk factors or atypical presentations. Lymph node biopsy should be considered for palpable nodes, especially those larger than 2 cm. Abdominal computed tomography or chest radiography may be important in patients with tumors or suspected visceral involvement.Differential Diagnosis

In its early stages, CTCL may resemble any of a number of benign inflammatory disorders (e.g., drug reaction, eczema, psoriasis, or contact dermatitis). These disorders should be ruled out before contemplating therapy.Staging

The staging of CTCL is based on an evaluation of the type and extent of skin lesions and the extent of lymph node, peripheral blood, and visceral involvement.70,71 Early disease is characterized by limited patch or plaque disease (stage IA) or generalized patch or plaque disease without evidence of extracutaneous involvement (stages IB and IIA); more advanced disease is characterized by cutaneous tumors (stage IIB), extracutaneous disease (stage III), and extracutaneous disease involving either lymph nodes (stage IVA) or viscera (stage IVB).Treatment

Topical Therapy

Topical therapy is the mainstay of the treatment of early disease (stage IA, IB, and IIA). Early aggressive therapy with radiation and chemotherapy has not proved to be superior to local approaches in controlling disease or improving survival in patients with limited disease.66,67 A rational approach for treating early limited (or histologically equivocal) disease is topical corticosteroids.73 Topical nitrogen mustard (mechlorethamine), in either aqueous or ointment form, is the most frequently used topical chemotherapy. In one series, the overall response rate to nitrogen mustard was 83%, with a complete response rate of 50%, after a median treatment time of 12 months.74 Median time to relapse was also 12 months.74

Carmustine (BCNU) solution, applied daily to lesions, is another useful regimen. Treatment generally lasts 8 to 16 weeks but has been continued for up to 6 months. Because systemic absorption can result in bone marrow suppression, complete blood counts must be monitored.62 Bexarotene, a topical retinoid, has been shown to be effective in CTCL; it is approved by the FDA for use in CTCL.75

Ultraviolet Radiation

Radiation therapy for CTCL takes several forms, from ultraviolet light to ionizing radiation. UVB is useful in stage I disease. In a retrospective study of 21 patients with stage I disease, narrow-band UVB led to complete remission in 81% of patients and to partial remission in 19%; the mean relapse-free interval was 24.5 months.76

Another effective approach to treatment of CTCL is the combination of psoralen and UVA (PUVA). In one study, 65% of patients with stage I CTCL had complete clinical clearing, with a mean relapse-free interval of 43 months; the disease-free survival rates at 5 and 10 years for stage IA were 56% and 30%, respectively.77 In another study, complete remission was observed in 71% of early-stage patients; in this study, the mean relapse-free interval was 22.8 months.76

Radiation Therapy

Total skin electron beam (TSEB) radiation delivers radiotherapy to the skin surface without a significant internal dose. It is especially useful with plaque disease. Typical doses are 2,400 to 3,600 cGy, fractionated over several weeks with 4 to 9 MeV electron beam radiation.78 Treatment responses are related to CTCL stage79; early-stage (stage IA) patients have a 95% response rate, but 50% will experience relapse within 10 years. TSEB may also be useful in stage IB disease (90% remission rate), but two thirds of patients treated with this modality will experience relapse within 5 years.73 Patients with tumor-stage (stage IIB) CTCL may receive effective palliation from TSEB, especially in combination with other therapies.79

Systemic Therapy

Systemic therapy has been undertaken as primary therapy in advanced CTCL (stages III through IVB); in early-stage disease, systemic therapy is used as part of sequential therapy to promote more durable responses.66,67

Oral bexarotene has yielded response rates of up to 45% in advanced CTCL, and it is approved by the FDA for use in this disease.80 Another systemic therapy used in the treatment of advanced CTCL is denileukin diftitox [DAB(389) IL-2].81 This receptor-targeted cytotoxic fusion protein binds to the IL-2 receptor on T cells; it achieved a 30% response rate in heavily-pretreated patients.81

Extracorporeal photopheresis, which is an accepted therapy for advanced CTCL, appears most useful in erythrodermic CTCL and Sézary syndrome.66,67 In this treatment, the patient is given a photoactivating drug (8-methoxypsoralen), the patient's white blood cells are collected via leukapheresis and irradiated with UVA, and the irradiated cells are returned to the patient intravenously. Advanced CTCL characterized by cutaneous tumors (stage III) or visceral involvement (stage IV) has also been treated with single-agent and combination chemotherapy using methotrexate, adenosine analogues, interferon alfa, and retinoids.66,67,82

Combination Therapy

Early aggressive treatment using TSEB followed by combination chemotherapy provides no survival advantage over sequential topical therapy.83,84 In a randomized controlled trial, 103 patients with MF received TSEB followed by either parenteral chemotherapy with cylophosphamide, doxorubicin, etoposide, and vincristine or sequential topical treatment. Patients receiving combined therapy had a significantly higher rate of complete response than those receiving sequential topical therapy; however, there was no difference in the rates of disease-free and overall survival between the two groups after a mean follow-up of 75 months.83 In an uncontrolled study, multimodality therapy was examined in patients with early and advanced disease. In this study, 95 CTCL patients received in consecutive phases of therapy interferon alfa and oral isotretinoin, TSEB, and maintenance therapy consisting of topical nitrogen mustard and interferon alfa. Patients with advanced disease also received six cycles of combination chemotherapy before TSEB. Although multimodality therapy resulted in high response rates (85% response, 60% complete response), the study provided no evidence that this form of combination therapy could improve the overall survival rates currently achieved with sequential topical therapy.80 In general, the heterogeneity of reported combination therapy regimens in CTCL makes it virtually impossible to compare results.

Future Directions

A number of experimental approaches are being investigated in CTCL, including allogeneic bone marrow transplantation, histone deacetylase inhibitors, monoclonal antibodies, and fusion toxins.67 Other investigative modalities include cytokines such as recombinant IL-12 and IL-2.66Complications

The most serious complications of CTCL are infections. Sepsis from ulcerated cutaneous tumors is a common cause of death. Visceral CTCL may occur, as may transformation to large cell lymphoma in some CTCL patients (39% probability after 12 years).71 In long-term survivors with early disease, local therapies (e.g., TSEB or PUVA) may contribute to the development of other skin cancers (e.g., BCC or SCC) and cataracts.85Prognosis

Many different attempts have been made to classify CTCL into useful prognostic groups. An early and still valid study that used the TNM system identified three major groups: good-risk patients (stages IA, IB, and IIA, with plaque-only skin disease and no lymph node, blood, or visceral involvement [median survival, > 12 years]); intermediate-risk patients (stages IIB, III, and IVA, with cutaneous tumors, erythroderma, or plaque disease and node or blood involvement but no visceral disease or node effacement [median survival, 5 years]); and poor-risk patients (stage IVB, with visceral involvement or node effacement [median survival, 2.5 years]).70

Eosinophilia is also associated with shortened survival.70 Other long-term studies have revealed that stage IA patients do not have a reduced life expectancy and that fewer than 10% of these patients experience disease progression to more advanced stages.86 Survival of patients with generalized patch/plaque MF (stage IB or IIA), at a median of 11.7 years, is significantly worse than that of a race-, age-, and sex-matched control population.87 Gender and race appear to have no effect on survival, but older patients (> 58 years) have shorter disease-specific survivals.68

Click here to subscribe or purchase the full chapter. Halpern, Allan C; Myskowski, Patricia L, 2 Dermatology, X Malignant Cutaneous Tumors, ACP Medicine Online, Dale DC; Federman DD, Eds. WebMD Inc., New York, 2000. http://www.acpmedicine.com/ Disclaimer

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Allan C. Halpern, MD, Professor, Joan and Sanford I. Weill Medical College of Cornell University, Chief, Department of Dermatology, Memorial Sloan-Kettering Cancer Center

Patricia L. Myskowski, MD, Joan and Sanford I. Weill Medical College of Cornell University

ACP Medicine Online.  2002; ©2002 WebMD Inc.


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